The mechanisms by which diabetes and chronic hyperglycemia increase the risk of macrovascular disease are unknown. The proposed study is designed to explore possible mechanisms in the Insulin Resistance Atherosclerosis Study (IRAS) cohort, a NHLBI-funded epidemiologic study. The overall objective of this study is to characterize the cross-sectional relationships between glycemia and macrovascular disease and to determine whether these relationships are mediated by factors related to glycemia. Both structural and functional manifestations of macrovascular disease will be assessed via measures of carotid intimal-medial wall thickness and brachial endothelium-mediated vasodilation. The potential mediating factors to be studied include abnormal lipoprotein concentration and composition, hyperinsulinemia, insulin resistance and thrombosis. The IRAS cohort is a group of 1625 men and women of three race/ethnic groups who were initially examined in 1993 in four U.S. centers. Participants were recruited to represent a range of glucose tolerance from normal glycemia to frank NIDDM. Atherosclerosis was assessed at the baseline examination via high resolution B-mode ultrasound imaging of the carotid arteries. Insulin sensitivity was assessed using the 'frequently sampled intravenous glucose tolerance test' (FSIGT) approach with minimal model analysis. These measures, as well as numerous additional factors for atherosclerosis (e.g., lipids and lipoproteins, thrombosis factors), will be assessed again at the time of follow-up examination of the IRAS cohort to be conducted in 1998. The current application proposes to supplement the IRAS follow-up examination, in a subset of 400 original cohort members, with additional measures of glycemia, its metabolic correlates, and a functional measure of macrovascular disease (brachial endothelium-mediated vasodilation). The study will include approximately equal numbers of diabetics, persons with impaired glucose tolerance, and normoglycemics who are participants in two of the four IRAS centers. Additional measures will include blood levels of glycated hemoglobin, serum-AGE peptide (an advanced glycation end product), oxidized LDL, and glycated LDL. The investigators note that identifying the mechanisms by which glycemia leads to impaired endothelial function and atherosclerosis may yield strategies for the prevention of diabetic macrovascular disease.